JP2022513011A - Continuous flow synthesis of cannabidiol - Google Patents

Abstract

A method for synthesizing cannabidiol of the formula (1) is disclosed herein. In this method, a solution [solution (S1)] of (+)-p-mentha-dien-3-ol of the formula (4) or an ester thereof and oliver of the formula (3) is used as a solution of a non-supporting Lewis acid [solution (solution (S1). S2)] and contact in a continuous flow reactor, and the resulting mixture is treated with a basic solution. The method provides the advantage that it can be conveniently carried out on an industrial scale while avoiding the formation of anomalous CBD and THC (Δ9-tetrahydrocannabinol).

Description

The present invention relates to a method for synthesizing cannabidiol.

Cannabidiol (CBD) of formula (1), the major non-psychotropic phytocannabinoid contained in most cannabis preparations, has been found to have antiepileptic, anxiolytic and antidystonian properties in humans. ing.

Cannabis sativa is currently the most used source of CBD, but due to the expected rapid growth of CBD demand, direct synthesis of CBD is desired. The most efficient pathway to CBD synthesis is trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid, as disclosed in Lago-Fernandez et al. Methods in enzymology, Vol. 593, 237-257 (2017). Equation (2): In the presence of an acid such as BF ₃ -etherate (BF ₃ -Et ₂ O) or a weak acid:

で示される（＋）－ｐ－メンタ－ジエン－１－オールと式（３）：

(+)-P-mentor-diene-1-all and formula (3):

で示されるオリベトールとの縮合、及び式（４）：

Condensation with olivetol represented by, and formula (4) :.

で示される（＋）－ｐ－メンタ－ジエン－３－オールとオリベトール（３）との縮合である。

It is a condensation of (+)-p-menthadiene-3-ol and olivetol (3) indicated by.

Such an approach is two undesired products, equation (5) :.

で示される非天然ＣＢＤ異性体（異常ＣＢＤ）及び式（６）：

Unnatural CBD isomer (abnormal CBD) represented by and formula (6):

で示される向精神性フィトカンナビノイドのΔ^９－テトラヒドロカンナビノール（ＴＨＣ）のかなりの量の形成につながる。

It leads to the formation of a significant amount of the psychotropic phytocannabinoid ^Δ9 -tetrahydrocannabinol (THC) indicated by.

The formation of THC in excess of statutory limits, which varies from country to country, and the fact that THC is associated with acute psychosis complicates the production of CBD by chemical synthesis from a regulatory standpoint.

Moreover, due to the lack of selectivity, the yield of CBD provided by the available synthetic pathways is too low for industrial use. As the sole title of the example, Petrzilka et al. [Helvetica Chimica Acta, 52, 4, (1969), 123, 1102] reported a yield of about 20% for CBD.

The problem of THC formation has already been investigated by Baek, S. et al. (Tetrahedron Letters, Vol.26, No. 8, pp 1083-1086, 1985), but they are BF ₃ supported on alumina or silica. Reaction of (+)-p-mentor-dien-1-ol (2) with olivetol (3) in the presence of -Et ₂ O reduces the formation of THC and at the same time yields the molar yield of CBD. It was discovered that the rate could be improved up to 55%. When the same conditions are applied to (+)-p-menthadiene-3-ol (2) and olivetol (3) (Lumir et al., Org. Biomol. Chem., 2005, 3, 1116-1123), CBD Yield dropped to 44%, but no THC was formed. In 1993, Baek S. et al. (Bull. Korean Chem. Soc., Vol. 14, No. 2, 1993) found that it is appropriate to use alumina-supported BF ₃ -Et ₂ O for the preparation of oliver. It was discovered that, in the absence of alumina, the reaction yield was low due to the cyclization reaction. On the other hand, the use of non-commercially available alumina-supported BF ₃ -Et ₂ O impairs the CBD production process for several reasons: 1) needs to be prepared in situ prior to the reaction 2 ) Due to the use of alumina in excess of 10 times compared to the actual catalyst (BF ₃ -Et ₂ O), the environmental E value (total waste / product ratio) increases. 3) It cannot be reused.

Therefore, there is still a need for a method of synthesizing CBD that can overcome the above drawbacks and at the same time reduce the formation of THC.

On the other hand, the use of continuous flow reactors, especially microreactors, in the chemical industry has increased significantly in recent years due to their high heat transfer capacity, high mixing speed and their operational flexibility.

Description of the Invention The applicant, surprisingly, continued the reaction of (+)-p-mentor-dien-3-ol (4) with olivetol (3) in the presence of unsupported Lewis acid as a catalyst. When performed in a flow reactor, it was found that CBD was obtained with a molar yield of 34% and no THC formation. Even more surprisingly, the ester of (+)-p-mentor-diene-3-ol (4), especially the formula (7) :.

で示されるアセチルエステル［酢酸（＋）－ｐ－メンタ－ジエン－３－オール］及びオリベトール（３）を非担持ルイス酸と連続フロー反応器内で反応させると、５１％の収率が得られる。

When the acetyl ester [acetic acid (+)-p-mentha-diene-3-ol] and oliver (3) shown in (3) are reacted with unsupported Lewis acid in a continuous flow reactor, a yield of 51% is obtained. ..

Therefore, the present invention is a method for synthesizing CBD, and the following steps:
a) A solution [solution (S1)] of (+)-p-menthadiene-3-ol (4) or an ester thereof and oliver (3) and a solution of unsupported Lewis acid [solution (S2)] are continuously connected. Contact in a flow reactor to obtain a first mixture [mixture (M1)] containing CBD; and b) contact the mixture (M1) with a basic solution [solution (S3)] for a second. To obtain a mixture of [mixture (M2)];
c) Concerning a method comprising separating CBD from a mixture (M2).

For the purposes of the present invention:
-The expression "continuous flow reactor" refers to an elongated tube for carrying a reagent stream, which has a cross-sectional dimension small enough to allow highly efficient heat conduction with its surroundings. It is long enough to achieve the desired residence time of the reagent stream. Typically, the cross-sectional dimensions of the tube range from 0.2 mm to 1 cm, while the length ranges from 10 cm to 30,000 cm. Microreactors suitable for carrying out the methods of the invention are manufactured by Sigma Aldrich. The expression "reagent flow" refers to a mixture of reagents, solutions, and reaction components that includes reactants and products flowing through the tubes of a reactor;
-Unless otherwise noted, general terms and expressions refer back to or fall within those general terms and expressions, with all and their preferred terms and expressions set forth in the description. Include;
-Lewis acid is a compound or ionic species having an empty orbital capable of accepting electron pairs from a donor compound; a suitable Lewis acid for carrying out the present invention is BF ₃ ; more preferably BF ₃ Is used in the form of BF ₃ -Et ₂ O;
-The expression "unsupported Lewis acid" means that Lewis acid is not immobilized on any other solid carrier, such as silica or alumina, with the aim of maximizing the surface area of the catalyst;
-If a range is indicated, the ends of the range are included.

In step a) of the method of the present invention, the solution (S1) and the solution (S2) are simultaneously pumped into the coil through the connector by the first and second pumps of the reactor, where they react to produce the mixture (M1). Form.

The solution (S1) has a molar ratio of 1: 1 to 1: 2, preferably a molar ratio of (+)-p-menthadiene-3-ol (4) or an ester thereof, preferably 1 to 1. Esters with linear or branched carboxylic acids having 5 carbon atoms, more preferably esters with acetic acid (acetate esters) (7) and olivettel (3), and organic solvents (C ₁ -C) selected from the following. It is composed of a trichlorinated solvent _, preferably dichloromethane, an ether solvent, preferably a methyl tert-butyl ether, an alkyl ester, preferably an ethyl acetate), wherein the concentration of each solute is 0.5 M to 0.01 M, respectively. The range is preferably 0.05 M, while the solution (S2) is the same as the solvent contained in Lewis acid, preferably BF ₃ , more preferably BF ₃ -esterate, and solution (S1). Also composed of organic solvents which may be different. Preferably, the solutions (S1) and (S2) contain the same solvent, preferably a solvent which is dichloromethane. The concentration of Lewis acid in the solution (S2) is in the range of 0.05M to 0.001M, preferably 0.005M. The solutions (S1) and (S2) are delivered at a flow rate of 0.1 to 1 mL / min, preferably 0.9 to 1.1 mL / min, and more preferably 1 mL / min, respectively.

The reaction temperature varies from −20 ° C. to 40 ° C., preferably 20 ° C.

When (+)-p-mentor-diene-3-ol (4) is used, the residence time of the mixture (M1) in the microreactor varies from 1 minute to 15 minutes, preferably 8 minutes. When the ester of (4) is used, especially when acetic acid (+)-p-mentor-diene-3-ol (7) is used, the residence time of the mixture (M1) in the microreactor is 1 to 10 minutes. It changes with, preferably 7 minutes.

In step b), contact between the mixture (M1) and the solution (S3) can be achieved by quenching the mixture (M1) flowing out of the reactor outlet in the solution (S3) in a container. .. Alternatively, the mixture (M1) can be carried with the solution (S3) to another continuous flow reactor. The solution (S3) is typically an alkali metal bicarbonate aqueous solution or an alkali metal carbonate aqueous solution, preferably sodium bicarbonate or potassium aqueous solution, and more preferably a sodium bicarbonate aqueous solution. The concentration of alkali metal bicarbonate or carbonate in the solution (S3) is typically in the range of 1-30% w / w, preferably the solution (S3) is in the alkali metal bicarbonate. It is saturated. By "saturation" is meant containing the maximum amount of bicarbonate or carbonate at room pressure and room temperature.

Step c) can be carried out by a method known in the art. Isolation is typically achieved by column chromatography.

The present invention will be described in more detail in the section of experiments below.

Experimental section material (+)-p-menthadiene-3-ol (4) was obtained according to R. Marin Barrios et al. Tetrahedron 2012, 68, 1105-1108.
Olivetol (3) was obtained from Sigma Aldrich.
Acetic acid (+)-p-menthadiene-3-ol (7) was obtained according to Prasav and Dav, Tetrahedron 1976, 32, 1437-1441.
Dichloromethane and sodium bicarbonate were obtained from Sigma Aldrich.

Methods All exemplary synthesis reported below was performed using Bohlender ™ PTFE tubes (inner diameter 0.8 mm, 16.91 m) purchased from Sigma Aldrich.
Analysis of CBD was performed by gas chromatography (GC) according to Gambaro et al. Analytica Chimica Acta 468 (2002) 245-254.

Synthesis example

Example 1-Synthesis of CBD from-(+)-p-mentor-diene-3-ol (4) and olivetol (3) 0.05M (+)-p-mentor-diene-3 in dichloromethane (10 mL) -A solution of oar (4) and 0.05 M olivetol (3) (S1) and a solution of BF ₃ -etherate 0.005 M (10 mol%) in dichloromethane (10 mL) (S2), 0.5 mL / for each pump. It was pumped simultaneously into the T-connector at a flow of minutes and then passed through an 8.5 mL reactor coil maintained at 20 ° C. The effluent was directly quenched with a saturated aqueous solution of sodium bicarbonate (100 mL). No THC was detected and CBD was isolated by column chromatography with a recovery of 34% mol.

Example 2-Synthesis of CBD from -acetic acid (+)-p-mentor-dien-3-ol (7) and olivetol (3) 0.05M acetic acid (+)-p-mentor-diene in dichloromethane (10 mL) A solution of -3-ol (7) and 0.1 M olivetol (3) and a solution of BF ₃ -etherate 0.005 M (10 mol%) in dichloromethane (10 mL) at a flow rate of 0.5 mL / min for each pump. It was pumped simultaneously into the T-connector and then passed through an 8.5 mL reactor coil maintained at 20 ° C. The effluent was directly quenched with a saturated aqueous solution of sodium bicarbonate (100 mL). No THC was detected and CBD was isolated with a recovery rate of 51% mol.

Claims (11)

Equation (1):

It is a method for synthesizing cannabidiol shown by the following step:
a) Equation (4):

(+)-P-menta-diene-3-ol or its ester represented by and formula (3):

The solution of oliver toll [solution (S1)] and the solution of unsupported Lewis acid [solution (S2)] shown in ]; And b) contact the mixture (M1) with a basic solution [solution (S3)] to obtain a second mixture [mixture (M2)];
c) A method comprising separating cannabidiol from the mixture (M2). The method according to claim 1, wherein the ester of (+)-p-mentha-diene-3-ol of the formula (4) is an ester with a linear or branched carboxylic acid having 1 to 5 carbon atoms. .. Esther has the formula (7):

The method according to claim 2, wherein the acetate is an acetate. The method of claim 1, 2 or 3, wherein the Lewis acid is BF ₃ . The method according to any one of claims 1 to 4, wherein the solutions (S1) and (S2) contain dichloromethane as a solvent. Claims 1 to 1, wherein the molar ratio of (+)-p-menthadiene-3-ol or an ester thereof of the formula (4) to olivetol of the formula (3) is in the range of 1: 1 to 1: 2. The method according to any one of 5. The method according to any one of claims 1 to 6, wherein the basic solution (S3) is an aqueous solution of an alkali metal carbonate or a bicarbonate. The method according to claim 7, wherein the basic solution (S3) is a sodium bicarbonate or potassium solution. The method according to claim 8, wherein the basic solution (S3) is a sodium bicarbonate solution. The method according to any one of claims 1 to 9, wherein step b) is achieved by quenching the mixture (M1) in a solution (S3) in a container. The method according to any one of claims 1 to 9, wherein step b) is achieved by transporting the mixture (M1) to another continuous flow reactor together with the solution (S3).